Volume 26, Issue 1, Pages 115-139 (March 2003)

8 of 15

FULL TEXT

FULL-TEXT PDF (151 KB)

Detection and management of comorbidity in patients with schizophrenia☆

Article Outline

• Detecting and managing psychiatric comorbidity in patients with schizophrenia

• Depressive disorders

• Detection and management of depressive disorders

• Obsessive-compulsive symptoms

• Detection and management of obsessive-compulsive symptoms

• Comorbid substance abuse

• Detection and management of substance abuse

• Suicide

• Detection and management of suicidality

• Detection and management of medical comorbidity

• Detecting and managing lifestyle factors

• Cigarette smoking

• HIV and hepatitis risks

• Exercise and diet

• Detecting and managing antipsychotic medication side effects

• Hyperprolactinemia

• Weight gain, diabetes, and hyperlipidemia

• Summary

• References

• Copyright

Schizophrenia is associated with substantial psychiatric and medical comorbidity [1], [2], [3]; approximately 50% of patients with schizophrenia have at least one comorbid psychiatric or medical condition [3], [4], [5], [6]. Comorbid psychiatric disorders, such as substance use disorder, often have a deleterious effect on the course of schizophrenia, and comorbid medical conditions, such as diabetes, may contribute to a decreased life span in patients with schizophrenia. As the overall ability to treat schizophrenia has improved with the introduction of the novel antipsychotic drugs, negative effects of comorbidity seem to have become more obvious [7]. The detection and management of comorbid conditions in this patient population are essential if the general outcome of patients is to be optimized.

Some comorbid conditions may have a genetic link to schizophrenia itself, and establishing whether patients with schizophrenia are at increased risk for certain genetic disorders may further understanding of psychosis. Preliminary evidence indicates an increased prevalence of schizophrenia and bipolar disorder in adults with velocardiofacial syndrome, a condition associated with small deletions of chromosome 22q11 [8]. Chromosome 22q11 contains the gene for catechol-O-methyltransferase, an enzyme involved in the degradation of dopamine [9]. Dysregulated dopamine transmission has long been thought to play an important role in the pathophysiology of psychosis [10], and recent studies suggest that polymorphisms at the catechol-O-methyltransferase gene may impair prefrontal cognitive function and increase the risk of psychotic symptoms [11].

Other comorbid conditions may provide clues about the neurobiology of schizophrenia itself. Green and colleagues [12] proposed a neurobiologic hypothesis suggesting that the high rates of substance use disorders observed in patients with schizophrenia may be related to dysfunctional dopamine-mediated mesocorticolimbic brain reward pathways in these individuals. Despite the presence of physiologic alterations in endocrine and immune function in psychotic patients that seem to result in reduced resistance to certain diseases [13], patients with schizophrenia also seem to be relatively protected against rheumatoid arthritis [14].

Some comorbid illnesses are likely based on lifestyle factors (eg, poor diet, lack of exercise, and cigarette smoking) [15]; others may be partly iatrogenic and linked to treatment, such as tardive dyskinesia, hyperprolactinemia, and weight gain, with their associated medical illnesses. Although psychiatry is becoming increasingly able to control the symptoms of schizophrenia and improve some of the cognitive deficits seen in these patients, identifying and managing the associated comorbidities remain major challenges. This article addresses many important comorbid conditions: depression, obsessive-compulsive (OC) symptoms, substance use disorder, suicide, hyperprolactinemia, weight gain, and diabetes.

Detecting and managing psychiatric comorbidity in patients with schizophrenia

Although the hierarchical system for psychiatric diagnosis tends to limit the concurrent diagnosis of Axis I disorders, such as depression and OC disorder, in patients with schizophrenia [6], studies suggest that co-occurring psychiatric syndromes are seen in up to one half of these patients [3], [6], [16]. Although it is unclear whether these coexisting syndromes represent distinct comorbidity or additional symptom dimensions of a heterogeneous disorder, evidence suggests that these syndromes are useful predictors of outcome and are potentially treatable [17].

Depressive disorders

Although schizophrenia is conceptualized as a nonaffective psychotic syndrome, it is often associated with a variety of depressive states, ranging from dysphoria to major depression. According to the Epidemiological Catchment Area study, people with schizophrenia have a 14 times greater risk of having a depressive disorder than the general population [16]; the National Comorbidity Study found an 81% lifetime risk of depression in patients with schizophrenia [16] compared with a risk of 7% to 25% in the general population [18]. Some have viewed depression as a part of schizophrenia per se [19], [20]; others have suggested it can be an expression of or response to severe psychosis [20] and likely to improve with treatment of psychosis [21], [22]; still others have ascribed it to a postpsychotic state, occurring after the resolution of psychotic symptoms [23].

The literature is divided over the prognostic significance of depressive symptoms in patients with schizophrenia. Some studies suggest that they are predictive of a good outcome [19], whereas others suggest the opposite [24], [25]. Depression in chronic schizophrenia has been associated with a risk of relapse [25] and suicide [26]. Koreen and colleagues [21] found, however, that although up to 75% of patients with first-episode schizophrenia had depressive symptoms at baseline, nearly all of these depressive symptoms resolved as the psychosis remitted.

Detection and management of depressive disorders

Detecting depression in patients with schizophrenia requires an understanding of the range of depressive states that these patients are likely to experience and of the common conditions (eg, negative symptoms or medication side effects) that may be confused with depression. Determining the temporal appearance, duration, and severity of depressive symptoms is important in formulating an appropriate treatment plan.

Several authors noted that depressive symptoms occurring during exacerbations of schizophrenia improve as the psychosis remits [21], [22], [23]. Nonetheless, enduring symptoms meeting criteria for major depression are thought to occur at some point in the lifetime of 60% of patients with schizophrenia [27]. Approximately 10% to 30% of patients with schizophrenia-spectrum illness meet criteria for schizoaffective disorder [28]; in patients with schizoaffective, depressed type, symptoms of depression are present for a substantial proportion of the total duration of the psychotic illness. Postpsychotic depression, meeting criteria for major depression, is reported to occur in approximately 30% to 50% of patients [23], [29]; it classically emerges after the resolution of psychotic symptoms and is seen most commonly after the first episode of schizophrenia [21], [23]. According to Iqbal and colleagues [29], patients who have postpsychotic depression feel a greater sense of loss, are more self-critical, have a lower self-esteem, and have better insight into their illness than patients without it.

Other clinically significant depressive phenomena, such as dysphoria and demoralization, frequently occur in patients with schizophrenia [29], [30]. Dysphoria, which includes symptoms of depression and anxiety, may occur at any point in the illness and seems to be associated with psychosocial stress [31] and positive symptoms [32]. Demoralization, which occurs as patients struggle with their illness and its effect on their functioning [30], seems to be associated with high performance expectations and insight into the illness and with hopelessness, low self-esteem, and suicidal thoughts [33]. Classic vegetative symptoms of depression may not be present in patients with demoralization and dysphoria [33].

The negative symptoms of schizophrenia, including affective flattening, alogia, avolition, apathy, anhedonia, and asociality, easily can be mistaken for depression [20], [23], [30]; in addition, antipsychotic side effects, such as sedation and akinesia (or other extrapyramidal system effects), may mimic depression [34]. Although some authors suggest that depression may overlap with or worsen negative symptoms [35], others do not [36], [37]. In distinguishing depression from negative symptoms, the diagnosis should be based on the presence of a core depressed mood and related neurovegetative symptoms and not on symptoms of flatness and anhedonic indifference without mood changes [19].

The management of depressive symptoms within schizophrenia depends on when they appear during the course of the disorder, their severity, and their persistence. Treatment may include pharmacologic and psychosocial interventions [38]. Because depressive symptoms may herald psychotic relapse, emergence of depressive symptoms should alert the clinician to the need to assess symptoms of psychosis. As reviewed by Levinson and colleagues [39], most treatment studies of depressive symptoms during an acute schizophrenic episode show that typical antipsychotics alone are as effective as when they are combined with antidepressants or lithium. More recent evidence suggests that compared with typical antipsychotics, atypical agents may be more efficacious in acutely psychotic patients with a comorbid mood disorder, including patients with schizoaffective disorder [40], [41], [42]. The treatment of major depression that occurs after the remission of psychosis may rely, however, on combinations of antipsychotics and antidepressants or mood stabilizers or both [39]. Although antidepressants seem to be of little value in treating depression with acute psychosis, tricyclics and serotonin reuptake inhibitors may have a role in the treatment of postpsychotic depression meeting criteria for major depression [43], [44], [45]. There is little support in the literature, however, for the routine use of antidepressants in the treatment of subsyndromal depressive symptoms or demoralization [29], [39]; psychosocial interventions, including stress reduction, problem-solving skills, job training, cognitive therapy, and support, may be more effective interventions for such symptoms [38].

Obsessive-compulsive symptoms

Obsessive compulsive (OC) symptoms in patients with schizophrenia have been documented in several well-designed studies with an estimated prevalence of 3.5% to 46% [3], [17], [46], [47]. Although the wide range in prevalence is likely to reflect inconsistent definitions for these symptoms, most contemporary studies report rates between 10% and 25% [3], [48]. OC symptoms in patients with schizophrenia are important to identify because they seem to have prognostic significance, and they may be differentially responsive to conventional versus specialized treatments.

Distinguishing between delusions, obsessions, ruminations, and preoccupations can be difficult in patients with thought disorder [46]. Classic teaching describes delusions as ego-syntonic and actively embraced by the patient, whereas obsessions are typically ego-dystonic and recognized as pathologic intrusions [49]. This distinction does not always hold true in clinical interviews of patients with psychosis. Obsessions and delusions seem to lie on a continuum of insight [46], and in patients with schizophrenia, delusions and obsessions may be overlapping [50]. Hwang and Opler [49] identified three patterns of OC symptoms in patients with schizophrenia: patients with long-standing OC symptoms preceding the onset of psychosis, patients with new-onset OC symptoms developing at or after the onset of schizophrenia, and patients with transient OC symptoms over the course of schizophrenic illness.

Although some authors have considered OC symptoms in these patients a defense against “personality disintegration” and a positive prognostic indicator [51], several more recent studies suggest that OC symptoms in schizophrenia are associated with greater psychopathology and worse outcome. Patients with OC symptoms tend to be more socially isolated, have longer hospitalizations, and be less treatment responsive than patients without this symptom complex [17], [49]. Some [52], [53], but not all [54], authors found that patients with schizophrenia and OC symptoms have more positive and negative symptoms than patients without OC symptoms. Several authors suggested an association between OC symptoms and neurocognitive dysfunction in schizophrenia [49], [53], [54]. In a study of 30 patients with schizophrenia, Berman and coworkers [54] found that patients with OC symptoms performed worse than patients without OC symptoms on measures of visuospatial skills, delayed verbal memory, and cognitive shifting abilities; the severity of OC symptoms correlated with poor performance on these cognitive tasks. Patients with OC disorder show deficits in similar cognitive tasks [55]. Nonetheless, it is unclear whether OC symptoms are related causally to OC disorder or whether they represent characteristics of a distinct subtype of schizophrenia [56].

Detection and management of obsessive-compulsive symptoms

The types of obsessions and compulsions experienced by patients with schizophrenia are similar to those found in classic OC disorder—contamination obsessions, hand-washing rituals, and counting and checking compulsions [47]. Several contemporary studies reliably used the Yale-Brown Obsessive-Compulsive Scale [57] to detect OC symptoms in patients with schizophrenia.

Typical antipsychotic medications seem to be of limited value in the treatment of OC symptoms in schizophrenia [58]. Emerging data suggest, however, that serotonin reuptake inhibitors added to typical antipsychotics can be used successfully in patients with schizophrenia and OC symptoms [59]. A review [60] of several small (and mostly open) trials using adjunctive clomipramine, imipramine, or fluoxetine found that 67.2% of patients showed improvement in OC symptoms with no worsening of psychosis, whereas 19% showed worsening of psychosis. In a small double-blind, crossover study of adjunctive clomipramine and placebo, Berman and colleagues [59] showed clomipramine was superior to placebo when added to typical anti psychotics in the treatment of obsessions and compulsions, and improved overall schizophrenic symptoms. Clinicians considering such an augmentation strategy should be aware that some serotonin reuptake inhibitors can increase some antipsychotic blood levels and should be used carefully.

The data regarding the role of atypical antipsychotics in patients with schizophrenia and OC symptoms are contradictory and still limited [16]. Several case reports indicate that atypical antipsychotics, with their combined dopamine D2 and serotonin 5-HT2 antagonism, may exacerbate or cause OC symptoms in patients with schizophrenia [61], [62], [63], although this phenomenon has not been shown in a controlled trial [64]. Case reports also suggest that serotonin reuptake inhibitors may be added effectively to an atypical antipsychotic to target OC symptoms in patients with schizophrenia [65]. A report suggests that the atypical antipsychotic risperidone may enhance treatment response in some patients with OC disorder [66].

Although cognitive behavioral therapy has a role in the treatment of OC disorder [67], to the authors' knowledge nonpharmacologic approaches to OC symptoms in schizophrenia have not been studied systematically. The potential value of cognitive behavioral therapy in this patient population may be influenced by a patient's level of cognitive function and degree of insight [68]. Given the frequency of OC symptoms in schizophrenia, more work is necessary to clarify their clinical correlates and prognostic significance and optimal treatment strategies.

Comorbid substance abuse

The lifetime prevalence of alcohol or substance use disorder (abuse or dependence) in patients with schizophrenia ranges from 10% to 60% [69]. The Epidemiologic Catchment Area study reported that 47% of patients with schizophrenia have a serious problem with substance use during their lifetime compared with 16% of the general population [70]. Rates of nicotine use in these patients have been reported to range from 58% to 90% [71]. Excluding nicotine, alcohol use disorder is the most frequent co-occurring disorder in schizophrenia [72]. Of illicit substances, patients with schizophrenia preferentially use cannabis [73], although cocaine abuse is also common, especially in the inner cities [74]. Similar to the general population, men are disproportionately represented among patients who use substances [75].

The use of drugs and/or alcohol complicates the course of illness and the treatment for patients with schizophrenia. For these individuals, even regular use of fairly small amounts of alcohol can have negative effects [76]. Patients who are comorbid for schizophrenia and substance use are at increased risk for infectious diseases, such as HIV, hepatitis B, and hepatitis C [77]. The use of alcohol and drugs is associated with treatment noncompliance, clinical exacerbations and poorer global functioning, relapse, an increased rate of hospitalizations, and higher rates of homelessness [72], [78], [79], [80], [81]. Comorbid alcohol and drug use worsens the course of illness for all patients with schizophrenia, including patients in their first episode [82]. Cannabis use disorder is reported in more than 50% of first-episode patients [83], and the use of cannabis in this population may cloud the diagnosis of a psychotic disorder and lengthen the time before treatment is initiated [84]. The financial and emotional toll of an already devastating illness is compounded by a comorbid alcohol or drug use disorder [85].

Several authors have proposed a “self-medication” hypothesis to explain the use of alcohol and other substances by patients with schizophrenia—to lessen negative symptoms and extrapyramidal system side effects of antipsychotic medications [86], [87]. Although nicotine and substances of abuse may decrease negative symptoms and extrapyramidal system effects [88], these apparent beneficial effects may not be causally related to the substance use. Two groups reported that patients with fewer negative symptoms use substances more frequently [89], [90]; in addition, first-episode patients, who have not yet had exposure to antipsychotic treatment, are likely to use substances.

As an extension of the self-medication hypothesis, based on findings from animal studies [91], Green and colleagues [12] proposed a neurobiologic formulation, suggesting that the high rates of comorbid alcohol and substance use disorders in these patients may relate to a deficiency in their dopamine-mediated mesocorticolimbic brain reward circuits and to the ability of alcohol and substances of abuse to ameliorate this deficiency. A related formulation regarding the vulnerability to substance abuse in patients with schizophrenia has been proposed by Chambers and colleagues [92]. In patients with schizophrenia, alcohol and drugs may reduce negative symptoms and extrapyramidal effects, while enhancing the brain reward systems by acting to improve the “signal detection” capability of dopamine-rich systems [12], [93], [94].

Detection and management of substance abuse

Substance abuse is often neither detected nor addressed in mental health settings [95]. In part, this situation may be due to the traditional separation between mental health and substance abuse services. Clinicians should ask patients about use of drugs and alcohol, understanding that use may be denied. Screening can be assisted through the use of standardized measures, especially instruments specifically developed for patients with mental illness (eg, the Dartmouth Assessment of Lifestyle Instrument [96]). When possible, clinicians also should pursue collateral reports from family members, case managers, and others involved in the delivery of services to the patient.

Patients with schizophrenia and a comorbid alcohol or substance use disorder require specialized treatment for both disorders [97]. This can be accomplished in a number of ways: sequential treatment, parallel treatment, or integrated treatment of the disorders [98]. Integrated treatment programs generally are accepted as the preferred method of treatment by patients and clinicians [76]. Such programs deliver psychosocial treatment and substance abuse services and provide medication management [99]. Drake and associates [100] noted that the effective treatment of these patients involves (1) staged interventions (tailored to the patient's degree of willingness to engage in treatment), (2) assertive outreach [101], (3) motivational interviewing [102], (4) comprehensive services (including medication management) [98], [100], (5) social support intervention, and (6) a long-term perspective (eg, an understanding that treatment takes place over months and years).

Pharmacotherapy for patients is still evolving, and there is no standardized treatment approach that meets the needs of all patients [103], [104]. Pharmacologic agents can be used to decrease symptoms of schizophrenia and improve overall functioning; a few agents may lead to in a decrease in substance use (see later). Optimally, medications serve to potentiate psychosocial treatments, and psychosocial treatments can serve to increase medication compliance.

Patients with comorbid substance abuse tend to respond poorly to typical antipsychotics. Although these medications are effective for the underlying psychosis, their side effects may cause patients to use drugs and alcohol in an attempt to diminish these effects [87]. The novel antipsychotics may have important advantages for these patients however because they produce fewer extrapyramidal symptoms, are more effective in reducing at least some negative symptoms, and may improve cognitive dysfunction [105], [106]. The medication that has received the most attention for its utility in patients with comorbid substance use is the novel antipsychotic clozapine.

Several anecdotal reports suggesting that clozapine may limit drug and alcohol use in patients have appeared in the literature. These case reports have described clozapine's apparent ability to reduce alcohol use [107], substance use [108], cocaine craving [109], and cigarette smoking [110]. Two preliminary studies from the authors' group, one naturalistic [111] and the other retrospective [112], showed greater than 70% reduction in alcohol use in patients taking clozapine to treat schizophrenia; striking reductions in use of cannabis (67–80%) and cocaine (80%) also were noted. The findings from the case reports and the studies of our group regarding the beneficial effects of clozapine have been supported further by reports from Buckley and colleagues [113] and Lee and associates [114].

Fewer data exist on the effects of other atypical antipsychotics in these patients. A retrospective study from the authors' group suggested that risperidone is less likely than clozapine to reduce alcohol and cannabis use [115]. Smelson and colleagues [116] reported, however, that risperidone seemed to help schizophrenic patients who used cocaine remain in treatment, reduce relapse, and have lower craving scores than patients treated with a typical neuroleptic. A report by Albanese [117] on bipolar patients with comorbid substance use disorders suggested that risperidone use was associated with maintenance of abstinence in these patients and a report by Brown and associates [118] suggested that, in a group of psychiatric patients with comorbid stimulant abuse, quetiapine was associated with decreased craving for cocaine. To the authors' knowledge, there are no data available on whether olanzapine, ziprasidone, or aripiprazole limit alcohol or substance use in these patients.

Although many studies are under way to investigate the potential role of pharmacotherapy in people with alcohol or other substance use disorders (but who do not have schizophrenia), few agents have been studied in patients with schizophrenia and comorbid alcohol and substance use disorders. Disulfiram has been used with safety and some success in this patient population [119], although it must be used with caution because of its potential ability to increase psychosis [120]. Three groups [121], [122], [123] have reported that naltrexone may have some value in decreasing alcohol in comorbid patients. Lastly the tricylic antidepressants, desipramine or imipramine, have been shown in preliminary studies to have a potential role in comorbid patients, especially patients with comorbid cocaine disorder [124], [125].

Suicide

Although suicide is a problem for the general population (the ninth leading cause of death in the United States), among people with schizophrenia it is the leading cause of premature death [126]. Nearly 50% of patients with schizophrenia attempt suicide, and their lifetime risk of suicide is 10% [127], a risk 10-fold higher than in the general population, as high as patients with affective disorders [128].

Suicide in patients with schizophrenia has been associated with hopelessness and a sense of disappointment over failure to meet high expectations [129]. It has been suggested that suicide by patients with schizophrenia can be a “nonpsychotic reaction to a severe illness” [130]. This notion is supported by data suggesting that patients with higher levels of awareness of their illness are at increased risk for suicide [131].

One of the strongest predictors of suicide in these patients is having a history of previous suicide attempts [132], [133]. As in the general population, male gender also seems to be a risk factor [133]; men with schizophrenia commit suicide at an earlier age than women [132]. Drake and Cotton [134] found that patients with schizophrenia who succeed in a suicide attempt are more depressed and isolated than those who do not. The risk of suicide risk is elevated after discharge from a psychiatric hospitalization [133] and can remain elevated for the first 3 months after discharge [132]. Patients who kill themselves have been found to have been more “improved” on discharge from the hospital, although they tended to have returned to more isolated living arrangements [26].

An early age of onset of schizophrenia has been found to be a risk factor for suicide [135], and the early phase of illness is a time of increased risk [130]. Suicide most often occurs during the active phase of the illness [136]. Patients with prominent negative symptoms may have a reduced risk for suicide compared with patients with positive symptoms, especially suspiciousness and delusions [137]. Although substance abuse is an established risk factor for suicide in the general population [138], to date, it has not been clearly shown to be a risk factor among patients with schizophrenia [135]. Kaplan and Harrow [139] found that poor overall functioning is a risk factor for suicide in patients with schizophrenia.

Detection and management of suicidality

The detection of suicidal ideation in patients with schizophrenia can be difficult. Suicide in schizophrenia can be an impulsive act, which makes prediction difficult [140]. Schizophrenic patients who kill themselves may not disclose their intentions in advance [141], and they tend to chose highly lethal methods for suicide [136]. Studies of this population found that 49% to 96% of patients had been seen by a health care professional within 3 months of committing suicide [136], and at least half had been seen the week before their suicide [132].

Harkavy-Friedman and Nelson [142] suggested that psychosocial and biologic issues be addressed carefully when working with schizophrenic patients presenting with suicidal behavior. Because discharge from the hospital can lead to social isolation [26], follow-up treatment is essential. Services should be set up before discharge. When the patient is discharged, intensive outreach often is required to engage patients in treatment and to prevent the social isolation that can occur. Referral and engagement in day treatment can help address this isolation.

Psychopharmacologic interventions also need to be assessed. In a study of 88 patients with schizophrenia who died by suicide, Heilae and coworkers [143] found that more than half of the patients who committed suicide either were prescribed inadequate doses of neuroleptic treatment or were not compliant with treatment; an additional 23% were considered to be not responsive to treatment. Obviously, optimal treatment for psychosis and affective symptoms is essential, as is an attempt to limit alcohol and substance abuse.

Studies suggest that clozapine, an atypical antipsychotic, may decrease rates of suicide. Meltzer and Okayli [144] followed 88 treatment-resistant patients for 7 years and found that the number of patients with no suicidality increased with clozapine treatment (from 53% of the group before clozapine to 88% during treatment with clozapine). Moreover, a review of current and former users of clozapine found that clozapine reduced mortality, mostly through a decrease in the suicide rate [145]. Reid and associates [146], in a review of suicide rates in more than 30,000 patients, concluded that patients with schizophrenia or schizoaffective disorder who were treated with clozapine showed a substantially reduced risk of suicide. Lastly, in a study of over 900 patients with schizophrenia, Meltzer and colleagues [147] found that clozapine was more likely than olanzapine to decrease suicidality in patients at risk for suicide.

Psychoeducation may increase compliance with treatment, although there may be an increased risk for suicide in patients who have more awareness and understanding of their illness [131]. Listening to patient reports and subjective experience of their distress is crucial because it has been shown to be a predictor of suicide [148]. Optimal treatment for patients with schizophrenia who are at risk of suicide includes careful assessment of risk factors for suicide, the use of active outreach to engage patients, referral to day programs after discharge to address social isolation, and effective pharmacotherapy.

Detection and management of medical comorbidity

The rate of physical disease among patients with serious mental illness is increased compared with the general population [2], [149], [150]. Goldman [5] estimated that nearly 50% of patients with schizophrenia suffer from at least one comorbid medical condition; Allebeck and Wistedt [151] found a nearly twofold increase in overall mortality compared with the general population. Although patients with schizophrenia are at particular risk for suicide and accidental death, they also are at risk for premature death from comorbid medical conditions [7].

Increased incidence of cardiovascular, pulmonary, and infectious disorders has been reported in patients with schizophrenia compared with psychiatric and normal controls [152]. These patients also seem to be at risk for psychogenic polydipsia [153] and osteoporosis [154]. In a study surveying more than 700 patients with schizophrenia, Dixon and colleagues [4] described self-reported problems with “eyesight, teeth, high blood pressure, and bowels” to be the most commonly noted lifetime medical conditions. Of particular concern within this study was the finding that lifetime and current rates of diabetes mellitus were far greater than those seen in the general population. Patients with schizophrenia seem to be at increased risk for contracting HIV and hepatitis B and C [155]. Several studies report higher than expected death rates from cardiovascular, pulmonary, infectious, gastrointestinal, and endocrine disorders in patients with schizophrenia [150], [152], [156], [157], [158], [159].

Co-occurring illnesses in patients with schizophrenia often are undiagnosed or come to clinical attention at acute, or advanced, phases when the disease is severe, painful, or life-threatening [150], [160]. Patients with schizophrenia are less likely to receive adequate health care as a result of barriers that are related to the health care system (eg, lack of health insurance and stigmatization by health care providers) and to the patients themselves (eg, poor communication skills and nonadherence with treatment) [5]. Additionally, patients with schizophrenia may have increased pain tolerance compared with the general population [161]. This sensory deficit may lead to reduced reporting of physical problems and contribute to morbidity in these patients [2].

In addition to the systemic barriers to health care access and the intrinsic patient factors that may lead to increased medical comorbidity, certain lifestyle factors and the use of antipsychotic medications (with their attendant side effects) place patients at considerable risk for serious, at times life-threatening conditions. Fortunately, some of the unhealthy habits and medication side effects may be modified successfully with clinical intervention. It is important for the clinician to recognize and minimize these factors to improve the long-term health status of these vulnerable patients.

Detecting and managing lifestyle factors

Lifestyle factors, such as cigarette smoking, substance abuse, poor nutrition, and lack of exercise, may place patients with schizophrenia at increased risk for certain physical disorders [162]. Although some lifestyle factors may be secondary to isolation and poverty [163] and more difficult to impact, others may be altered with appropriate health promotion intervention.

Cigarette smoking

Cigarette smoking is the most preventable cause of death in society [164] and the prevalence of cigarette smoking in patients with schizophrenia is up to three times that found in the general population [15]. Not surprisingly, smoking-related disease seems to be more prominent among these patients than in the general population [156]. Some studies have suggested, however, that patients with schizophrenia have lower than expected cancer rates, particularly lung cancer [152]. Although this counterintuitive finding has led some investigators to speculate that schizophrenia may confer a selective advantage against cancer [165], this hypothesis is not yet substantiated [166]. Nonetheless, cardiovascular and pulmonary diseases, which typically are associated with cigarette smoking, consistently are reported to be the most frequent causes of medical comorbidity and mortality in patients with schizophrenia [151], [157], [158].

Although smoking cessation may be more difficult for people with schizophrenia than for others [167], clinicians still should discuss the hazards of smoking and encourage patients to reduce their cigarette consumption. Some evidence suggests that group therapy combined with a nicotine patch may be effective in helping patients with schizophrenia reduce smoking [168]. Cigarette smoking among these patients may be more than just a “bad habit,” however. One small study showed that haloperidol was associated with an increase in smoking and nicotine levels [169], whereas others suggest that switching treatment from typical antipsychotics to clozapine may lead to a decrease in smoking [110], [170]. A controlled study [168] suggested that atypical antipsychotic medications may facilitate smoking cessation more than typical agents. Data also are emerging about the beneficial effects of bupropion combined with psychotherapy on nicotine addiction in this patient population [171]. Pharmacologic and psychosocial interventions may be useful in assisting patients to reduce smoking and ultimately, it is hoped, smoking-related disease and mortality.

HIV and hepatitis risks

Although alcohol and substance abuse were discussed earlier, they may contribute independently to the increased rates of certain medical disorders in patients with schizophrenia, in particular HIV and hepatitis B and C [77], [172], [173]. Other behavioral factors, such as having multiple partners and engaging in unsafe sexual practices, may place patients with schizophrenia at increased risk for sexually transmitted diseases [174]. Clinicians should obtain information about patients' sexual practices, provide education about safe sex, and when indicated test for HIV and hepatitis. The psychiatric care of patients with schizophrenia and HIV/AIDS or hepatitis should occur in close collaboration with infectious disease or gastroenterology specialists.

Exercise and diet

Compared with the general population, patients with schizophrenia seem to exercise less and to eat a diet higher in fat and lower in fiber [162]. Data from the 1989 National Health Interview Survey (NHIS) indicated that individuals with schizophrenia have body mass index distributions similar to or higher than the general population [175]. Allison and colleagues [176] found that although there may be a small subpopulation of underweight patients with schizophrenia, as a whole, this population is as obese or more obese than people without schizophrenia; the prevalence of overweight and obesity in patients with schizophrenia is 40% to 62% and may be particularly high in women [176], [177]. Obesity may contribute to the increased rates of cardiovascular disease, type 2 diabetes, hypertension, dyslipidemia, and sleep apnea reported in patients with schizophrenia [178], [179], [180]. Although atypical antipsychotics produce clinically significant weight gain [181], [182] (see later), earlier studies (such as the NHIS) suggested that obesity among patients with schizophrenia was common before the widespread use of these medications. In addition to medication effects and patient-based endogenous factors, lifestyle factors, such as poor diet and lack of exercise, may play an important role in the development of obesity in these patients.

Detecting and managing antipsychotic medication side effects

Adverse effects of antipsychotic medications can increase medical morbidity. Waddington and coworkers [183] found that treatment with more than one antipsychotic concurrently was associated with reduced survival, although the causal link is not known. Although typical antipsychotics can cause extrapyramidal effects, tardive dyskinesia, and hyperprolactinemia, some atypical antipsychotics seem to cause medically significant weight gain and altered glucose and lipid metabolism [179], [181], [184], [185]. Additionally, some typical and atypical antipsychotics, such as thioridazine and ziprasidone, may prolong the QTc interval of the electrocardiogram, potentially increasing the risk of arrhythmia [186]. Although clozapine is the most effective treatment for schizophrenia, it carries the risk of causing agranulocytosis (0.4%) [187] and a risk that is greater than other antipsychotics of producing seizure (5% at moderate doses) [188]. Clozapine seems also to be associated with a rare (but increased) risk of myocarditis [189], [190].

Common antipsychotic medication side effects, including extrapyramidal effects and tardive dyskinesia, are well described in the literature [191], and a detailed discussion of them is beyond the scope of this article. Because the common endocrine and metabolic effects of these medications may contribute to the increased medical morbidity in patients with schizophrenia, however, further discussion of their detection and management is warranted here.

Hyperprolactinemia

Typical antipsychotics and risperidone have the potential to elevate serum prolactin levels, whereas several atypical antipsychotics are less likely to do so [192]. Although early studies of the long-term effects of antipsychotic-induced hyperprolactinemia reported few negative consequences of prolactin elevation [193], it is a topic that has received limited investigation. Hyperprolactinemia resulting from medical illness is known to produce galactorrhea, hypogonadism (evidenced by sexual and menstrual dysfunction and diminished gonadal hormone levels), and osteoporosis, all of which also have been reported in patients with schizophrenia [154], [194], [195], [196], [197]. With the exception of studies on galactorrhea [194], few investigations directly assessed the relationship between actual prolactin levels and these conditions in patients with antipsychotic-induced hyperprolactinemia. Interestingly, a few reports have failed tofind a close relationship between prolactin levels and sexual and menstrual dysfunction [195], [198], [199] or between prolactin and gonadal hormone levels [200].

Although the potential long-term health consequences of chronic antipsychotic-induced hyperprolactinemia have not been established firmly, clinicians should inquire about the possible adverse effects of hyperprolactinemia and aim to diminish them. Galactorrhea and sexual and menstrual dysfunction, associated with prolactin elevation, may be minimized by dose reduction or by a medication change to an antipsychotic with less prolactin-elevating potential [192], [201]. Moreover, case reports suggest that dopamine agonists (eg, bromocriptine and cabergoline), although they have the potential to worsen psychosis, may alleviate hyperprolactinemia and associated hypogonadism if added to typical antipsychotics or risperidone [202], [203]. Lastly, since sustained hyperprolactinemia can increase the risk for osteoporosis [154], patients who require long-term treatment with antipsychotics and have shown continued hyperprolactinemia may be appropriate candidates for screening with bone densiometry.

Weight gain, diabetes, and hyperlipidemia

Studies suggest that 50% of patients taking antipsychotic medication experience clinically significant weight gain [204]. As a class, atypical antipsychotics consistently have been shown to cause more weight gain than the typical agents [181], [205]. In a large meta-analysis comparing weight gain associated with a variety of atypical and typical antipsychotics, Allison and coworkers [181] found, after 10 weeks of treatment, a mean weight gain of 9.8 lb with clozapine, 9.1 lb with olanzapine, and 4.6 lb with risperidone compared with 2.4 lb with haloperidol. The authors found the atypical antipsychotic ziprasidone to be associated with less than a 1 lb weight gain and the typical agent molindone to be associated with a small weight loss. Antipsychotic-induced weight gain is usually most rapid in the acute phase of treatment, then tends to plateau after 1 to 2 years [206]. Younger patients and patients with a low baseline body mass index may be more susceptible to atypical antipsychotic-induced weight gain [207]. This noticeable and often unacceptable side effect may threaten medication compliance and increase obesity-related comorbidities, such as diabetes and serum lipid abnormalities [178], [181].

In addition to causing clinically significant weight gain, the atypical antipsychotics (especially clozapine and olanzapine) have been implicated in rare cases of ketoacidosis and in an increased risk of type 2 diabetes mellitus, a condition that is estimated to be twice as prevalent in patients with schizophrenia compared with the general population [179], [182], [208], [209]. Although clozapine is the most effective treatment for refractory schizophrenia, the cumulative incidence of diabetes among long-term clozapine patients may be as high as 35% [179]. It must be recognized, however, that although antipsychotics may result in impaired glucose tolerance and type 2 diabetes, especially in patients with other risk factors (eg, family history) [182], schizophrenia itself may be a risk factor for diabetes [209].

Obesity, including antipsychotic-induced obesity, also is associated with serum lipid abnormalities. Studies suggest that clozapine and olanzapine are associated with hypertriglyceridemia [179], [185]. The novel antipsychotic ziprasidone may be associated with a reduction of cholesterol and triglycerides, independent of changes in weight [210].

Detecting and managing weight gain and obesity-related conditions associated with atypical antipsychotic medications are essential to ensure optimal treatment outcome and to minimize iatrogenic medical comorbidity. Patients should be educated about the potential for weight gain, counseled about dietary choices, encouraged to exercise, and weighed frequently. Although data are limited, there is some suggestion that behavioral weight reduction programs that teach problem-solving skills and that use reinforcement (to compensate for cognitive deficits) and incremental approaches to behavioral change may be successful in patients with schizophrenia [178], [211], [212]. In a small study evaluating a Weight Watcher's program for patients with olanzapine-related weight gain, however, only the men experienced significant weight loss [213].

Use of some centrally acting weight loss drugs in this population theoretically is limited by their potential to increase biogenic amine activity and possibly to exacerbate symptoms of psychosis. An open trial of amantadine, used in 12 patients with olanzapine-associated weight gain, was well tolerated, however, and resulted in a 3.5-kg average weight loss [214]. Additionally, case reports described the successful use of nizatidine [215] and topiramate [216] in reducing weight gain associated with olanzapine and clozapine. Lastly, although there have been no clinical trials, there may be a potential role for the non–centrally acting weight control drug orlistat [178].

Because atypical antipsychotics seem to increase weight and potentially alter glucose and lipid metabolism, they should be administered with care in patients with risk factors for diabetes and cardiovascular disease. These patients may benefit from a baseline fasting glucose and lipid panel assessment, with follow-up monitoring and, if indicated, measurement of glycohemoglobin and glucose tolerance testing [179]. Patients who develop glucose intolerance or diabetes may require treatment with hypoglycemic agents, and patients with hyperlipidemia may require lipid-lowering agents. These simple interventions, which seem to be overlooked frequently by psychiatrists [179], may be important in minimizing the overall morbidity of patients with schizophrenia.

Summary

Approximately half of patients with schizophrenia have at least one comorbid psychiatric or medical condition, worsening prognosis and contributing to the high rate of morbidity and mortality. Depression is associated with suicide, the leading cause of premature death in patients with schizophrenia; obsessive-compulsive symptoms may worsen prognosis; alcohol and substance use disorders are associated with a poor outcome; and comorbid medical conditions, including cardiac and pulmonary disease, infectious diseases, diabetes, hyperlipidemia, hypogonadism, and osteoporosis, are often underrecognized and undertreated. The new generation of antipsychotic medications has improved the potential outcome of patients with schizophrenia. Providing optimal treatment for patients and fully realizing the potential of these new agents require focused attention on detection, recognition, and treatment of comorbid psychiatric and medical conditions in patients with schizophrenia.

References

[1]. [1] Simpson JC, Tsuang MT. Mortality among patients with schizophrenia. Schizophr Bull. 1996;22:485–499. MEDLINE

[2]. [2] Adler LE, Griffith JM. Concurrent medical illness in the schizophrenic patient: epidemiology, diagnosis, and management. Schizophr Res. 1991;4:91–107. MEDLINE | CrossRef

[3]. [3] Cassano GB, Pini S, Saettoni M, Rucci P, Dell'Osso L. Occurrence and clinical correlates of psychiatric comorbidity in patients with psychotic disorders. J Clin Psychiatry. 1998;59:60–68. MEDLINE

[4]. [4] Dixon L, Postrado L, Delahanty J, Fischer PJ, Lehman A. The association of medical comorbidity in schizophrenia with poor physical and mental health. J Nerv Ment Dis. 1999;187:496–502. MEDLINE | CrossRef

[5]. [5] Goldman LS. Medical illness in patients with schizophrenia. J Clin Psychiatry. 1999;60:10–15.

[6]. [6] Bermanzohn PC, Porto L, Arlow PB, Pollack S, Stronger R, Siris SG. Hierarchical diagnosis in chronic schizophrenia: a clinical study of co-occurring syndromes. Schizophr Bull. 2000;26:517–525. MEDLINE

[7]. [7] Brown S. Excess mortality of schizophrenia: a meta analysis. Br J Psychiatry. 1997;171:502–508. MEDLINE | CrossRef

[8]. [8] Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry. 1999;56:940–945. CrossRef

[9]. [9] Grossman MH, Emanuel BS, Budarf ML. Chromosomal mapping of the human catechol-O-methyl transferase gene to 22q11.1-q112. Genomics. 1992;12:822–825. MEDLINE | CrossRef

[10]. [10] Carlsson A. The current status of the dopamine hypothesis of schizophrenia. Neuropsychopharmacology. 1988;1:179–186. CrossRef

[11]. [11] Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, et al. Effect of COMT Va1108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA. 2001;98:6917–6922. MEDLINE | CrossRef

[12]. [12] Green AI, Zimmet SV, Strous RD, Schildkraut JJ. Clozapine for comorbid substance use disorder and schizophrenia: do patients with schizophrenia have a reward-deficiency syndrome that can be ameliorated by clozapine?. Harv Rev Psychiatry. 1999;6:287–296. MEDLINE | CrossRef

[13]. [13] Prior P, Hassall C, Cross KW. Causes of death associated with psychiatric illness. J Public Health Med. 1996;18:381–389. MEDLINE

[14]. [14] Eaton WE, Hayward C, Ram R. Schizophrenia and rheumatoid arthritis: a review. Schizophr Res. 1992;6:181–192. MEDLINE | CrossRef

[15]. [15] Dalack GW, Healy DJ, Meador-Woodruff JH. Nicotine dependence in schizophrenia: clinical phenomena and laboratory findings. Am J Psychiatry. 1998;155:1490–1501.

[16]. [16] Fenton WS. Comorbid conditions in schizophrenia. Curr Opin Psychiatry. 2001;14:17–23. CrossRef

[17]. [17] Fenton WS, McGlashan TH. The prognostic significance of obsessive-compulsive symptoms in schizophrenia. Am J Psychiatry. 1986;143:437–441.

[18]. [18] Gruenberg AM, Goldstein RD. Depressive disorders. In: Tasman A editors. Depressive disorders in psychiatry. Philadelphia: WB Saunders; 1997;p. 990–995.

[19]. [19] McGlashan TH, Carpenter WT. Postpsychotic depression in schizophrenia. Arch Gen Psychiatry. 1976;33:231–239.

[20]. [20] Sax KW, Strakowski SM, Keck PE, Upadhyaya VH, McElroy SL, West SA. Relationship among negative, positive, and depressive symptoms in schizophrenia and psychotic depression. Br J Psychiatry. 1996;168:68–71. MEDLINE | CrossRef

[21]. [21] Koreen AR, Siris SG, Chakos M, Alvir J, Mayerhoff D, Lieberman J. Depression in first-episode schizophrenia. Am J Psychiatry. 1993;150:1643–1648.

[22]. [22] Tollefson GD, Andersen SW, Tran PV. The course of depressive symptoms in predicting relapse in schizophrenia: a double-blind, randomized comparison of olanzapine and risperidone. Biol Psychiatry. 1999;46:365–373. Abstract | Full Text | Full-Text PDF (151 KB) | CrossRef

[23]. [23] Birchwood M, Iqbal Z, Chadwick P, Trower P. Cognitive approach to depression and suicidal thinking in psychosis: (1. ontogeny of post-psychotic depression). Br J Psychiatry. 2000;177:516–521. MEDLINE | CrossRef

[24]. [24] Siris SG. Diagnosis of secondary depression in schizophrenia: implications for DSM-IV. Schizophr Bull. 1991;17:75–98. MEDLINE

[25]. [25] Mandel MR, Severe JB, Schooler NR, Gelenberg AJ, Mieske M. Development and prediction of postpsychotic depression in neuroleptic-treated schizophrenics. Arch Gen Psychiatry. 1982;39:197–203.

[26]. [26] Drake RE, Gates C, Cotton PG. Suicide among schizophrenics: a comparison of attempters and completed suicides. Br J Psychiatry. 1986;149:784–787. MEDLINE | CrossRef

[27]. [27] Martin RL, Cloninger CR, Guze SB, Clayton PJ. Frequency and differential diagnosis of depressive syndromes in schizophrenia. J Clin Psychiatry. 1985;46:9–13. MEDLINE

[28]. [28] Siris SG, Lavin MR. Other psychotic disorders. In: Kaplan HI, Sadock BJ editor. Comprehensive textbook of psychiatry/VI. vol. 1:Baltimore: Williams & Wilkins; 1995;p. 1019–1025.

[29]. [29] Iqbal Z, Birchwood M, Chadwick P, Trower P. Cognitive approach to depression and suicidal thinking in psychosis: (2. testing the validity of a social ranking model). Br J Psychiatry. 2000;177:522–528. MEDLINE | CrossRef

[30]. [30] Siris SG. Depression in schizophrenia: perspective in the era of “atypical” antipsychotics. Am J Psychiatry. 2000;157:1379–1389. CrossRef

[31]. [31] Schwartz CC, Myers JK. Life events and schizophrenia. Arch Gen Psychiatry. 1977;34:1238–1241.

[32]. [32] Lysaker PH, Bell MD, Bioty SM, Zito WS. The frequency of associations between positive and negative symptoms and dysphoria in schizophrenia. Compr Psychiatry. 1995;36:113–117. | CrossRef

[33]. [33] Bartels SJ, Drake RE. Depressive symptoms in schizophrenia: Comprehensive differential diagnosis. Compr Psychiatry. 1988;29:467–483. CrossRef

[34]. [34] Siris SG. Akinesia and postpsychotic depression: a difficult differential diagnosis. J Clin Psychiatry. 1987;38:240–243.

[35]. [35] Siris SG, Adan F, Cohen M, Mandeli J, Aronson A, Casey E. Postpsychotic depression and negative symptoms: an investigation of syndromal overlap. Am J Psychiatry. 1988;145:1532–1537.

[36]. [36] Zisook S, McAdams LA, Kuck J, Harris MJ, Bailey A, Patterson TL, et al. Depressive symptoms in schizophrenia. Am J Psychiatry. 1999;156:1736–1743.

[37]. [37] Bottlender R, Straub A, Möller HJ. Prevalence and background factors of depression in first admitted schizophrenic patients. Acta Psychiatr Scand. 2000;101:153–160.

[38]. [38] Siris SG. Management of depression in schizophrenia. Psychiatr Ann. 2000;30:13–19.

[39]. [39] Levinson DF, Umapathy C, Musthaq M. Treatment of schizoaffective disorder and schizophrenia with mood symptoms. Am J Psychiatry. 1999;156:1138–1148.

[40]. [40] Tollefson GD, Sanger TM, Lu Y, Thieme ME. Depressive signs and symptoms in schizophrenia: a prospective blinded trial of olanzapine and haloperidol. Arch Gen Psychiatry. 1998;55:250–258. CrossRef

[41]. [41] Marder SR, Davis JM, Chouindard CH. The effects of risperidone on the five dimensions of schizophrenia derived by factor analysis: combined results of the North American trials. J Clin Psychiatry. 1997;58:538–546. MEDLINE

[42]. [42] Banov MD, Zarate CA, Tohen M, Scialabba D, Wines JD, Kolbrener M, et al. Clozapine therapy in refractory affective disorders: polarity predicts response in long-term follow-up. J Clin Psychiatry. 1994;55:295–300. MEDLINE

[43]. [43] Siris SG, Morgan V, Fagerstrom R, Rifkin A, Cooper TB. Adjunctive imipramine in the treatment of postpsychotic depression: a controlled trial. Arch Gen Psychiatry. 1987;44:533–539.

[44]. [44] Hogarty GE, McEvoy JP, Ulrich RF, DiBarry AL, Bartone P, Cooley S, et al. Pharmacotherapy of impaired affect in recovering schizophrenic patients. Arch Gen Psychiatry. 1995;52:29–41.

[45]. [45] Kirli S, Caliskan M. A comparative study of sertraline versus imipramine in postpsychotic depressive disorder of schizophrenia. Schizophr Res. 1998;33:103–111. Abstract | Full Text | Full-Text PDF (168 KB) | CrossRef

[46]. [46] Eisen JL, Beer DA, Pato MT, Venditto TA, Rasmussen SA. Obsessive-compulsive disorder in patients with schizophrenia or schizoaffective disorder. Am J Psychiatry. 1997;154:271–273.

[47]. [47] Tibbo P, Kroetsch M, Chue P, Warneke L. Obsessive-compulsive disorder in schizophrenia. J Psychiatr Res. 2000;34:139–146. MEDLINE | CrossRef

[48]. [48] Berman I, Berman SM, Lengua JA, Green AI. Obsessive and compulsive symptoms in chronic schizophrenia. Compr Psychiatry. 1995;36:6–10. | CrossRef

[49]. [49] Hwang MY, Opler LA. Management of schizophrenia with obsessive-compulsive disorder. Psychiatr Ann. 2000;30:23–28.

[50]. [50] Bermanzohn PC, Porto L, Arlow PB, et al. Obsessions and delusions: separate and distinct or overlapping?. CNS Spectrums. 1997;2:58–61.

[51]. [51] Rosen I. The clinical significance of obsessions in schizophrenia. J Ment Sci. 1956;103:773–785.

[52]. [52] Hwang MY, Morgan JE, Losconzey MF. Clinical and neuropsychological profiles of obsessive-compulsive schizophrenia: a pilot study. J Neuropsychiatry Clin Neurosci. 2000;12:91–94. MEDLINE

[53]. [53] Lysaker PH, Marks KA, Picone JB, Rollins AL, Fastenau PS, Bond GR. Obsessive and compulsive symptoms in schizophrenia: clinical and neurocognitive correlates. J Nerv Ment Dis. 2000;188:78–83. MEDLINE | CrossRef

[54]. [54] Berman I, Merson A, Viegner B, Losonczy MF, Pappas D, Green AI. Obsessions and compulsions as a distinct cluster of symptoms in schizophrenia: a neuropsychological study. J Nerv Ment Dis. 1998;186:150–156. MEDLINE | CrossRef

[55]. [55] Schmidtke K, Schorb A, Winkelmann G, Hohagan F. Cognitive frontal lobe dysfunction in obsessive-compulsive disorder. Biol Psychiatry. 1998;43:666–673. Abstract | Full Text | Full-Text PDF (55 KB) | CrossRef

[56]. [56] Berman I, Chang HH, Klegon DA. Obsessive-compulsive symptoms in schizophrenia: neuropsychological perspectives. Psychiatr Ann. 1999;29:525–528.

[57]. [57] Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, et al. The Yale-Brown Obsessive Compulsive Scale: (I. development, use, and reliability). Arch Gen Psychiatry. 1989;46:1006–1011.

[58]. [58] Poyurovsky M, Dorfman-Etrog P, Hermesh H, Munitz H, Tollefson GD, Weizman A. Beneficial effects of olanzapine in schizophrenic patients with obsessive-compulsive symptoms. Int Clin Psychopharmacol. 2000;15:169–173. MEDLINE | CrossRef

[59]. [59] Berman I, Sapers B, Chang H, Losonczy M, Schmilder J, Green A. Treatment of obsessive-compulsive symptoms in schizophrenic patients with clomipramine. J Clin Psychopharmacol. 1995;15:206–210. MEDLINE | CrossRef

[60]. [60] Chang HH, Berman I. Treatment issues for patients with schizophrenia who have obsessive-complusive symtoms. Psychiatric Annals. 1999;29:529–532.

[61]. [61] Baker RW, Chengappa KN, Baird JW, Steingard S, Christ MA, Schooler NR. Emergence of obsessive compulsive symptoms during treatment with clozapine. J Clin Psychiatry. 1992;53:439–442. MEDLINE

[62]. [62] Kopala L, Honer WG. Risperidone, serotonergic mechanisms, and obsessive-compulsive symptoms in schizophrenia. Am J Psychiatry. 1994;151:1714–1715.

[63]. [63] Morrison D, Clark D, Goldfarb E, McCoy L. Worsening of obsessive-compulsive symptoms following treatment with olanzapine. Am J Psychiatry. 1998;155:855.

[64]. [64] Baker RW, Ames D, Umbricht DS, Chengappa KN, Schooler N. Obsessive-compulsive symptoms in schizophrenia: a comparison of olanzapine and placebo. Psychopharmacol Bull. 1996;32:89–93. MEDLINE

[65]. [65] Strous RD, Patel JK, Zimmet S, Green AI. Clozapine and paroxetine in the treatment of schizophrenia with obsessive-compulsive features. Am J Psychiatry. 1999;156:973–974.

[66]. [66] McDougle CJ, Epperson CN, Pelton GH, Wasylink S, Price LH. A double-blind, placebo-controlled study of risperidone addition in serotonin reuptake inhibitor-refractory obsessive-compulsive disorder. Arch Gen Psychiatry. 2000;57:794–801. CrossRef

[67]. [67] van Balkom AJ, de Haan E, van Oppen P, Spinhoven P, Hoogduin KA, van Dyck R. Cognitive and behavioral therapies alone versus in combination with fluvoxamine in the treatment of obsessive compulsive disorder. J Nerv Ment Dis. 1998;186:492–499. MEDLINE | CrossRef

[68]. [68] Goff DC. The comorbidity of obsessive-compulsive disorder and schizophrenia. Psychiatr Ann. 1999;29:533–536.

[69]. [69] Mueser KT, Yarnold PR, Levinson DF, Singh H, Bellack AS, Kee K, et al. Prevalence of substance abuse in schizophrenia: demographic and clinical correlates. Schizophr Bull. 1990;16:31–56. MEDLINE

[70]. [70] Regier DA, Farmer ME, Rae DS, Locke BZ, Keith SJ, Judd LL, et al. Comorbidity of mental disorders with alcohol and other drug abuse. JAMA. 1990;264:2511–2518. MEDLINE

[71]. [71] Hughes JR, Hatsukami DK, Mitchell JE, Dahlgren LA. Prevalence of smoking among schizophrenic outpatients. Am J Psychiatry. 1986;143:993–997.

[72]. [72] Drake RE, Mueser KT. Alcohol-use disorder and severe mental illness. Alcohol Health Res World. 1996;20:87–93.

[73]. [73] Selzer JA, Lieberman JA. Schizophrenia and substance abuse. Psychiatr Clin North Am. 1993;16:401–412.

[74]. [74] Sevy S, Kay SR, Opler LA, van Praag HM. Significance of cocaine history in schizophrenia. J Nerv Ment Dis. 1990;178:642–648. MEDLINE | CrossRef

[75]. [75] Mueser KT, Bennett M, Kushner MG. Epidemiology of substance use disorders among persons with chronic mental illness. In: Lehman AF, Dixon LB editor. Double jeopardy: chronic mental illness and substance use disorders. Netherlands: Harwood Academic Publishers; 1995;p. 9–25.

[76]. [76] Drake RE, Mueser KT. Substance abuse comorbidity. In: Lieberman JA, Murray RM editor. Comprehensive care of schizophrenia. London: Martin Dunitz; 2001;p. 243–254.

[77]. [77] Cournos F, Bakalar N. AIDS and people with severe mental illness: a handbook for mental health professionals. New Haven, CT: Yale University Press; 1996; p. 346.

[78]. [78] Hurlburt MS, Hough RL, Wood PA. Effects of substance abuse on housing stability of homeless mentally ill persons in supported housing. Psychiatr Serv. 1996;47:731–736. MEDLINE

[79]. [79] Dixon L, Haas G, Weiden P, Sweeney J, Frances A. Acute effects of drug abuse in schizophrenic patients: clinical observations and patients' self reports. Schizophr Bull. 1990;16:69–79. MEDLINE

[80]. [80] Soni S, Sobell M. Alcohol abuse in chronic schizophrenics: implications for management in the community. Acta Psychiatry Scand. 1991;84:272–276.

[81]. [81] Negrete JC, Knapp WP, Douglas DE, Smith WB. Cannabis affects the severity of schizophrenic symptoms: results of a clinical survey. Psychol Med. 1986;16:515–520. MEDLINE | CrossRef

[82]. [82] Grech A, Van Os J, Murray RM. Influence of cannabis on the outcome of psychosis. Schizophr Res. 1999;36:41. Full-Text PDF (93 KB)

[83]. [83] Rolfe TJ, McGory P, Cooks J, Longley T, Plowright D. Cannabis use in first episode psychosis: incidence and short-term outcome. Schizophr Res. 1999;36:313.

[84]. [84] Addington J. Early intervention strategies for co-morbid cannabis use and psychosis. Presented at the Inaugural International Cannabis and Psychosis Conference. Melbourne, 1999.

[85]. [85] Dickey B, Azeni H. Persons with dual diagnoses of substance abuse and major mental illness: their excess costs of psychiatric care. Am J Public Health. 1996;86:973–977. MEDLINE | CrossRef

[86]. [86] Khantzian EJ. A self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence. Am J Psychiatry. 1985;142:1259–1264.

[87]. [87] Siris SG. Pharmacological treatment of substance-abusing schizophrenic patients. Schizophr Bull. 1990;16:111–122. MEDLINE

[88]. [88] Glynn SH, Sussman S. Why patients smoke. Hosp Community Psychiatry. 1990;41:1027–1028. MEDLINE

[89]. [89] Lysaker P, Bell M, Beam-Goulet J, Milstein R. Relationship of positive and negative symptoms to cocaine abuse in schizophrenia. J Nerv Ment Dis. 1994;182:109–112. MEDLINE | CrossRef

[90]. [90] Buchanan RW, Strauss ME, Breier A, Kirkpatric B, Carpenter WT. Attentional impairments in deficit and nondeficit forms of schizophrenia. Am J Psychiatry. 1997;154:363–370.

[91]. [91] Svensson TH, Mathe MH, Anderson JL, Nomikos GG, Hildebrand BE, Marcus M. Mode of action of atypical neuroleptics in relation to the phencyclidine model of schizophrenia. J Clin Psychopharmacol. 1995;15:11S–18S. MEDLINE

[92]. [92] Chambers AR, Krystal JH, Self DW. A neurobiological basis for substance abuse comorbidity in schizophrenia. Biol Psychiatry. 2001;50:71–83. Abstract | Full Text | Full-Text PDF (263 KB) | CrossRef

[93]. [93] Fadda F, Mosca E, Colombo G, Gessa GL. Effects of spontaneous ingestion of ethanol on brain dopamine metabolism. Life Sci. 1989;44:281–287. MEDLINE | CrossRef

[94]. [94] Goeders NE, Smith JE. Reinforcing properties of cocaine in the medial prefrontal cortex: primary action on presynaptic dopaminergic terminals. Pharm Biochem Behav. 1986;25:191–199.

[95]. [95] Ananth J, Vandewater S, Kamal M, Brodsky A, Gamal R, Miller M. Missed diagnosis of substance abuse in psychiatric patients. Hosp Community Psychiatry. 1989;40:297–299. MEDLINE

[96]. [96] Rosenberg SD, Drake RE, Wolford GL, Mueser KT, Oxman TE, Vidaver RM, et al. Dartmouth Assessment of Lifestyle Instrument (DALI): a substance use disorder screen for people with severe mental illness. Am J Psychiatry. 1998;155:232–238.

[97]. [97] Bellack AS, DiClemente CC. Treating substance abuse among patients with schizophrenia. Psychiatr Serv. 1999;50:75–80. MEDLINE

[98]. [98] Osher FC, Kofoed LL. Treatment of patients with both psychiatric and psychoactive substance use disorders. Hosp Community Psychiatry. 1989;40:1025–1030. MEDLINE

[99]. [99] Minkoff K. An integrated treatment model for dual diagnosis of psychosis and addiction. Hosp Community Psychiatry. 1989;40:1031–1036. MEDLINE

[100]. [100] Drake RE, Essock SM, Shaner A, Carey KB, Minkoff K, Kola L, et al. Implementing dual diagnosis services for clients with severe mental illness. Psychiatr Serv. 2001;52:469–476. MEDLINE | CrossRef

[101]. [101] Ziedonis D, Williams J, Corrigan P, Smelson D. Management of substance abuse in schizophrenia. Psychiatr Ann. 2000;30:67–75.

[102]. [102] Drake RE, Mueser KT. Psychosocial approaches to dual diagnosis. Schizophr Bull. 2000;26:105–118. MEDLINE

[103]. [103] Wilkins JN. Pharmacotherapy of schizophrenia patients with comorbid substance abuse. Schizophr Bull. 1997;23:215–228. MEDLINE

[104]. [104] Krystal JH, D'Souza DC, Madonick S, Petrakis IL. Toward a rational pharmacotherapy of comorbid substance abuse in schizophrenic patients. Schizophr Res. 1999;35:35–49. Abstract | Full-Text PDF (1042 KB)

[105]. [105] Siegfried SL, Fleishchacker W, Lieberman JA. Pharmacological treatment of schizophrenia. In: Lieberman JA, Murray RM editor. Comprehensive care of schizophrenia. London: Martin Dunitz; 2001;p. 59–94.

[106]. [106] Harvey PD, Keefe RE. Cognition and the new antipsychotics. J Adv Schizophr Brain Res. 1998;1:2–8.

[107]. [107] Albanese MJ, Khantzian EJ, Murphy SL, Green AI. Decreased substance use in chronically psychotic patients treated with clozapine. Am J Psychiatry. 1994;151:780–781.

[108]. [108] Buckley P, Thompson P, Way L, Meltzer HY. Substance abuse among patients with treatment-resistant schizophrenia: characteristics and implications for clozapine therapy. Am J Psychiatry. 1994;151:385–389.

[109]. [109] Yovell Y, Opler LA. Clozapine reverses cocaine craving in a treatment-resistant mentally ill chemical abuser: a case report and a hypothesis. J Nerv Ment Dis. 1994;182:591–592. MEDLINE

[110]. [110] McEvoy JP, Freudenreich O, McGee M, VanderZwaag C, Levin E, Rose J. Clozapine decreases smoking in patients with chronic schizophrenia. Biol Psychiatry. 1995;37:550–552. Full-Text PDF (176 KB) | CrossRef

[111]. [111] Drake RE, Xie H, McHugo GJ, Green AI. The effects of clozapine on alcohol and drug use disorders among schizophrenic patients. Schizophr Bull. 2000;26:441–449. MEDLINE

[112]. [112] Zimmet SV, Strous RD, Burgess ES, Kohnstamm S, Green AI. Effects of clozapine on substance use in patients with schizophrenia and schizoaffective disorder: a retrospective survey. J Clin Psychopharmacol. 2000;20:94–98. MEDLINE | CrossRef

[113]. [113] Buckley P, McCarthy M, Chapman P, Richman C, Yamamoto B. Clozapine treatment of comorbid substance abuse in patients with schizophrenia. Schizophr Res. 1999;36:272.

[114]. [114] Lee ML, Dickson RA, Campbell M, Oliphant J, Gretton H, Dalby JT. Clozapine and substance abuse in patients with schizophrenia. Can J Psychiatry. 1998;45:855–856.

[115]. [115] Green AI, Burgess ES, Zimmet SV, Dawson R, Strous R. Alcohol and cannabis use in schizophrenia: effects of clozapine and risperidone. Schizophr Res (in press).

[116]. [116] Smelson DA, Williams J, Kaune M, Losonczy MF, Menza M, Ziedonis D. Reduced cue-elicited cocaine craving and relapses following treatment with risperidone. Presented at the American Psychiatric Association; Chicago, 2000.

[117]. [117] Albanese M. Risperidone in substance abusers with bipolar disorder. Presented at the 39th Annual Meeting of the American College of Neuropsychopharmacology. San Juan, Puerto Rico, 2000.

[118]. [118] Brown ES, Nejtek VA, Perantie DC. Neuroleptics and quetiapine in psychiatric illness with comorbid stimulant abuse. Presented at the 57th Annual Convention of the Society of Biological Psychiatry. Philadelphia, Pennsylvania, 2002.

[119]. [119] Kofoed L, Kania J, Walsh T, Tkinson R. Outpatient treatment of patients with substance abuse and coexisting psychiatric disorders. Am J Psychiatry. 1986;143:867–872.

[120]. [120] Kingsbury SJ, Salzman C. Disulfiram in the treatment of alcoholic patients with schizophrenia. Hosp Community Psychiatry. 1990;41:133–134. MEDLINE

[121]. [121] Maxwell S, Shinderman MS. Naltrexone in the treatment of dually diagnosed patients. J Addict Dis. 1997;16:125.

[122]. [122] Dougherty RJ. Naltrexone in the treatment of alcohol dependent dual diagnosed patients. J Addict Dis. 1997;16:107.

[123]. [123] Sernyak MJ, Glazer WM, Heninger GR, Charney DS, Woods SW, Petrakis IL, et al. Naltrexone augmentation of neuroleptics in schizophrenia. J Clin Psychopharmacol. 1998;18:245–251.

[124]. [124] Ziedonis D, Richardson T, Lee E, Petrakis I, Kosten T. Adjunctive desipramine in the treatment of cocaine abusing schizophrenics. Psychopharmacol Bull. 1992;28:309–314. MEDLINE

[125]. [125] Siris SG, Mason SE, Bermanzohn PC, Shuwall MA, Aseniero MA. Adjunctive imipramine in substance-abusing dysphoric schizophrenic patients. Psychopharmacol Bull. 1993;29:127–133. MEDLINE

[126]. [126] Black DW, Warrack G, Winokur G. The Iowa record-linkage study: (I. suicides and accidental deaths among psychiatric patients). Arch Gen Psychiatry. 1985;42:71–75.

[127]. [127] Tsuang MT, Fleming JA, Simpson JC. Suicide and schizophrenia. In: Jacobs DG editors. The Harvard Medical School guide to suicide assessment and intervention. San Francisco: Jossey-Bass; 1999;p. 287–299.

[128]. [128] Baxter D, Appleby L. Case register study of suicide risk in mental disorders. Br J Psychiatry. 1999;175:322–326. MEDLINE | CrossRef

[129]. [129] Westermeyer JF, Harrow M, Marengo JT. Risk for suicide in schizophrenia and other psychotic and nonpsychotic disorders. J Nerv Ment Dis. 1991;179:259–266. MEDLINE

[130]. [130] Drake RE, Gates C, Whitaker A, Cotton PG. Suicide among schizophrenics: a review. Compr Psychiatry. 1985;26:90–100. CrossRef

[131]. [131] Amador XF, Friedman JH, Kasapis C, Yale SA, Flaum M, Gorman JM. Suicidal behavior in schizophrenia and its relationship to awareness of illness. Am J Psychiatry. 1996;153:1185–1188.

[132]. [132] Roy A. Risk factors for suicide in psychiatric patients. Arch Gen Psychiatry. 1982;39:1089–1095.

[133]. [133] Rossau CD, Mortensen PB. Risk factors for suicide in patients with schizophrenia: nested case-control study. Br J Psychiatry. 1997;171:355–359. MEDLINE | CrossRef

[134]. [134] Drake RE, Cotton PG. Depression, hopelessness and suicide in chronic schizophrenia. Br J Psychiatry. 1986;148:554–559. MEDLINE | CrossRef

[135]. [135] Gupta S, Black DW, Arndt S, Hubbard WC, Andreasen NC. Factors associated with suicide attempts among patients with schizophrenia. Psychiatr Serv. 1998;49:1353–1355. MEDLINE

[136]. [136] Heilae H, Isometsae ET, Henriksson MM, Heikkinen ME, Marttunen MJ, Loennqvist JK. Suicide and schizophrenia: a nationwide psychological autopsy study on age- and sex-specific clinical characteristics of 92 suicide victims with schizophrenia. Am J Psychiatry. 1997;154:1235.

[137]. [137] Fenton WS, McGlashan TH, Victor BJ, Blyler CR. Symptoms, subtype, and suicidality in patients with schizophrenia spectrum disorders. Am J Psychiatry. 1997;154:199–204.

[138]. [138] Weiss R, Hufford M. Substance abuse and suicide. In: Jacobs DG editors. The Harvard Medical School guide to suicide assessment and intervention. San Francisco: Jossey-Bass; 1999;p. 300–310.

[139]. [139] Kaplan KJ, Harrow M. Positive and negative symptoms as risk factors for later suicidal activity in schizophrenics versus depressives. Suicide Life Threat Behav. 1996;26:105–121. MEDLINE

[140]. [140] Allebeck P. Schizophrenia: a life-shortening disease. Schizophr Bull. 1989;15:81–89. MEDLINE

[141]. [141] Earle KA, Forquer SL, Volo AM, McDonnell PM. Characteristics of outpatient suicides. Hosp Community Psychiatry. 1994;45:123–126. MEDLINE

[142]. [142] Harkavy-Friedman JM, Nelson E. Management of the suicidal patient with schizophrenia. Psychiatr Clin N Am. 1997;20:625–640.

[143]. [143] Heilae H, Isometsae ET, Henriksson MM, Heikkinen ME, Marttunen MJ, Loennqvist JK. Suicide victims with schizophrenia in different treatment phases and adequacy of antipsychotic medication. J Clin Psychiatry. 1999;60:200. MEDLINE

[144]. [144] Meltzer HY, Okayli G. Reduction of suicidality during clozapine treatment of neuroleptic-resistant schizophrenia: impact of risk-benefit assessment. Am J Psychiatry. 1995;152:183–190.

[145]. [145] Walker A, Lanaza L, Arellano F, Rothman K. Mortality in current and former users of clozapine. Epidemiology. 1997;8:671–677. MEDLINE | CrossRef

[146]. [146] Reid WH, Mason M, Hogan T. Suicide prevention effects associated with clozapine therapy in schizophrenia and schizoaffective disorder. Psychiatr Serv. 1998;49:1029–1033. MEDLINE

[147]. [147] Meltzer HY, Alphs L, Green AI, Altamura CA, Anand R, Bertoldi A, et al. Reduced suicidality in schizophrenia with clozapine treatment. Arch Gen Psychiatry (in press).

[148]. [148] Cohen LJ, Test MA, Brown RL. Suicide and schizophrenia: data from a prospective community treatment study. Am J Psychiatry. 1990;147:602–607.

[149]. [149] Koranyi EK. Morbidity and rate of undiagnosed physical illnesses in a psychiatric clinic population. Arch Gen Psychiatry. 1979;36:414–419.

[150]. [150] Munk-Jorgensen P, Mors O, Mortensen PB, Ewald H. The schizophrenic patient in the somatic hospital. Acta Psychiatr Scand. 2000;102:96–99. CrossRef

[151]. [151] Allebeck P, Wistedt B. Mortality in schizophrenia: a ten-year follow-up based on the Stockholm County inpatient register. Arch Gen Psychiatry. 1986;43:650–653.

[152]. [152] Tsuang MT, Perkins K, Simpson JC. Physical diseases in schizophrenia and affective disorder. J Clin Psychiatry. 1983;44:42–46. MEDLINE

[153]. [153] de Leon J, Verghese C, Tracy JI, Josiassen RC, Simpson GM. Polydipsia and water intoxication in psychiatric patients: a review of the epidemiological literature. Biol Psychiatry. 1994;35:408–419. Abstract | Full-Text PDF (1157 KB) | CrossRef

[154]. [154] Abraham G, Friedman RH, Verghese C. Osteoporosis demonstrated by dual energy x-ray absorptiometry in chronic schizophrenic patients. Biol Psychiatry. 1996;40:430–431. Full-Text PDF (206 KB) | CrossRef

[155]. [155] Rosenberg SD, Goodman LA, Osher FC, Swartz MS, Essock SM, Butterfied MI, et al. Prevalence of HIV, hepatitis B, and hepatitis C in people with severe mental illness. Am J Public Health. 2001;91:31–37. MEDLINE

[156]. [156] Brown S, Inskip H, Barraclough B. Causes of excess mortality of schizophrenia. Br J Psychiatry. 2000;177:212–217. MEDLINE | CrossRef

[157]. [157] Buda M, Tsuang MT, Fleming JA. Causes of death in DSM-III schizophrenics and other psychotics (atypical group): a comparison with the general population. Arch Gen Psychiatry. 1988;45:283–285.

[158]. [158] Mortensen PB, Juel K. Mortality and cause of death in schizophrenic patients in Denmark. Acta Psychiatr Scand. 1990;81:372–377. CrossRef

[159]. [159] Tsuang MT, Winokur G, Crowe RR. Morbidity risks of schizophrenia and affective disorders among first-degree relatives of patients with schizophrenia, mania, depression and surgical conditions. Br J Psychiatry. 1980;137:497–504. MEDLINE | CrossRef

[160]. [160] Koranyi EK. Physical health and illness in a psychiatric outpatient department population. Can Psychiatr Assoc J. 1972;17(Suppl 2):SS109.

[161]. [161] Dworken RH. Pain insensitivity in schizophrenia: a neglected phenomenon and some implications. Schizophr Bull. 1994;20:235–248. MEDLINE

[162]. [162] Brown S, Birtwistle J, Roe L, Thompson C. The unhealthy lifestyle of people with schizophrenia. Psychol Med. 1999;29:697–701. MEDLINE | CrossRef

[163]. [163] Winkleby M, Jatulis DE, Frank E, Fortmann SP. Socioeconomic status and health: how education, income, and occupation contribute to risk factors for cardiovascular disease. Am J Public Health. 1992;82:816–820. MEDLINE | CrossRef

[164]. [164] United States Department of Health and Human Services . Reducing the health consequences of smoking: 25 years of progress—a report of the Surgeon General. Rockville, MD: Centers for Disease Control; 1989;.

[165]. [165] Lichtermann D, Ekelund J, Pukkala E, Tanskanen A, Lonnqvist J. Incidence of cancer among persons with schizophrenia and their relatives. Arch Gen Psychiatry. 2001;58:573–578. CrossRef

[166]. [166] Jablensky A, Lawrence D. Schizophrenia and cancer: is there a need to invoke a protective gene. Arch Gen Psychiatry. 2001;58:579–580. CrossRef

[167]. [167] Covey L, Hughes DC, Glassman AH, Blazer DG, George LK. Ever-smoking, quitting, and psychiatric disorders: evidence from the Durham, North Carolina Epidemiologic Catchment Area. Tobacco Control. 1994;3:222–227. CrossRef

[168]. [168] George TP, Ziedonis DM, Feingold A, Pepper WT, Satterburg CA, Winkel J, et al. Nicotine transdermal patch and atypical antipsychotic medications for smoking cessation in schizophrenia. Am J Psychiatry. 2000;157:1835–1842. CrossRef

[169]. [169] McEvoy JP, Freudenreich O, Levin ED, Rose JE. Haloperidol increases smoking in patients with schizophrenia. Psychopharmacology. 1995;119:124–126. MEDLINE | CrossRef

[170]. [170] George TP, Sernyak MJ, Ziedonis DM, Woods SM. Effects of clozapine on smoking in chronic schizophrenic outpatients. J Clin Psychiatry. 1996;57:4–11.

[171]. [171] Weiner E, Ball MP, Summerfelt A, Gold J, Buchanan R. Effects of sustained-release bupropion and supportive group therapy on cigarette consumption in patients with schizophrenia. Am J Psychiatry. 2001;158:635–637. CrossRef

[172]. [172] Brenner LM, Karper LP, Krystal JH. Short-term use of disulfiram with clozapine. J Clin Psychopharmacol. 1994;14:313–314.

[173]. [173] Carol G, Smelson DA, Losonczy MF, Ziedonis D. Alcohol and drug abuse: a preliminary investigation of cocaine craving among persons with and without schizophrenia. Psychiatr Serv. 2001;52:1029–1031. MEDLINE | CrossRef

[174]. [174] Sewell DD. Schizophrenia and HIV. Schizophr Bull. 1996;22:465–473. MEDLINE

[175]. [175] United States Department of Health and Human Services. National health interview survey. CD-Rom Series 10; 1993

[176]. [176] Allison DB, Fontaine KR, Heo M, Mentore JL, Cappelleri JC, Chandler LP, et al. The distribution of body mass index among individuals with and without schizophrenia. J Clin Psychiatry. 1999;60:215–220. MEDLINE

[177]. [177] Stedman T, Welham J. The distribution of adipose tissue in female inpatients receiving psychotic drugs. Br J Psychiatry. 1993;162:249–250. MEDLINE | CrossRef

[178]. [178] Green AI, Patel JP, Goisman RM, Allison DB, Blackburn G. Weight gain from novel antipsychotic drugs: need for action. Gen Hosp Psychiatry. 2000;22:224–235. Abstract | Full Text | Full-Text PDF (190 KB) | CrossRef

[179]. [179] Henderson DC, Cagliero E, Gray CO, Nasrallah RA, Hayden D, Schoenfeld DA, et al. Clozapine, diabetes mellitus, weight gain, and lipid abnormalities: a five-year naturalistic study. Am J Psychiatry. 2000;157:975–981. CrossRef

[180]. [180] Winkelman JW. Schizophrenia, obesity, and obstructive sleep apnea. J Clin Psychiatry. 2001;62:8–11. MEDLINE

[181]. [181] Allison DB, Mentore JM, Heo M, Chandler L, Cappelleri JC, Infante M, et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry. 1999;156:1686–1696.

[182]. [182] Wirshing DA, Spellberg BJ, Erhart SM, Marder SR, Wirshing WC. Novel antipsychotics and new onset diabetes. Biol Psychiatry. 1998;44:778–783. Abstract | Full Text | Full-Text PDF (38 KB) | CrossRef

[183]. [183] Waddington JL, Youssef HA, Kinsella A. Mortality in schizophrenia: antipsychotic polypharmacy and absence of adjunctive anticholinergics over the course of a 10-year prospective study. Br J Psychiatry. 1998;173:325–329. MEDLINE | CrossRef

[184]. [184] Hagg S, Joelsson L, Mjorndal T, Spigset O, Oja G, Dahlqvist R. Prevalence of diabetes and impaired glucose tolerance in patients treated with clozapine compared with patients treated with conventional depot neuroleptic medications. J Clin Psychiatry. 1998;59:294–299. MEDLINE

[185]. [185] Osser DN, Najarian DM, Dufresne RL. Olanzapine increases weight and serum triglyceride levels. J Clin Psychiatry. 1999;60:767–770. MEDLINE

[186]. [186] Glassman AH, Bigger JT. Antipsychotic drugs: prolonged QTc interval, torsade de pointes, and sudden death. Am J Psychiatry. 2001;158:1774–1782. CrossRef

[187]. [187] Alphs LD, Anand R. Clozapine: the commitment to patient safety. J Clin Psychiatry. 1999;60:39–42.

[188]. [188] Devinsky O, Honigfeld G, Patin J. Clozapine-related seizures. Neurology. 1991;41:369–371. MEDLINE

[189]. [189] Kilian JG, Kerr K, Lawrence C, Celermajer DS. Myocarditis and cardiomyophathy associated with clozapine. Lancet. 1999;354:1841–1845. Abstract | Full Text | Full-Text PDF (123 KB) | CrossRef

[190]. [190] La Grenade L, Graham D, Trontell A. Myocarditis and cardiomyopathy associated with clozapine use in the United States. N Engl J Med. 2001;345:224–225. MEDLINE | CrossRef

[191]. [191] Casey DE, Keepers GA. Neuroleptic side effects: acute extrapyramidal syndromes and tardive dyskinesia. In: Casey DE, Christensen AV editor. Psychopharmacology: current trends. Berlin: Springer-Verlag; 1988;p. 74–93.

[192]. [192] Dickson RA, Glazer WM. Neuroleptic-induced hyperprolactinemia. Schizophr Res. 1999;35:s75–s86. Abstract | Full Text | Full-Text PDF (120 KB) | CrossRef

[193]. [193] Meltzer HY. Long-term effects of neuroleptic drugs on the neuroendocrine system. Adv Biochem Psychopharmacol. 1985;40:59–68. MEDLINE

[194]. [194] Windgassen K, Wesselmann U, Schulze-Monking H. Galactorrhea and hyperprolactinemia in schizophrenic patients on neuroleptics: frequency and etiology. Neuropsychobiology. 1996;33:142–146. CrossRef

[195]. [195] Ghadirian AM, Chouinard G, Annable L. Sexual dysfunction and plasma prolactin levels in neuroleptic-treated schizophrenic outpatients. J Nerv Ment Dis. 1982;170:463–467. MEDLINE

[196]. [196] Riecher-Rossler A, Hafner H, Stumbaum M, Maurer K, Schmidt R. Can estradiol modulate schizophrenic symptomatology?. Schizophr Bull. 1994;20:203–214. MEDLINE

[197]. [197] Yazigi RA, Quintero CH, Salameh WA. Prolactin disorders. Fertil Steril. 1997;67:215–225. Abstract | Full-Text PDF (1372 KB) | CrossRef

[198]. [198] Magharious W, Goff DC, Amico E. Relationship of gender and menstrual status to symptoms and medication side effects in patients with schizophrenia. Psychiatr Res. 1998;77:159–166.

[199]. [199] Prentice DS, Deakin JFW. Role of neuroleptic drugs and organic mechanisms in the aetiology of menstrual irregularities in schizophrenic women. Schizophr Res. 1992;6:114. Abstract | Full Text | Full-Text PDF (363 KB) | CrossRef

[200]. [200] Huber TJ, Rollnik J, Wilhelms J, von zur Muhlen A, Emrich HM, Schneider U. Estradiol levels in psychotic disorders. Psychoneuroendocrinology. 2001;26:27–53. Abstract | Full Text | Full-Text PDF (75 KB) | CrossRef

[201]. [201] Canuso C, Hana M, Jhamb KK, Green AI. Olazanpine use in women with antipsychotic-induced hyperprolactinemia. Am J Psychiatry. 1998;155:1458.

[202]. [202] Smith S. Neuroleptic-associated hyperprolactinemia: can it be treated with bromocriptine?. J Reprod Med. 1992;37:737–740. MEDLINE

[203]. [203] Tollin SR. Use of the dopamine agonist bromocriptine and cabergoline in the management of risperidone-induced hyperprolactinemia in patients with psychotic disorders. J Endocrinol Invest. 2000;23:765–770. MEDLINE

[204]. [204] Baptista T. Body weight gain induced by antipsychotic drugs: mechanisms and management. Acta Psychiatr Scand. 1999;100:3–16. CrossRef

[205]. [205] Wirshing DA, Wirshing WC. Novel antipsychotics: comparison of weight gain liabilities. J Clin Psychiatry. 1999;60:358–363. MEDLINE

[206]. [206] Stanton JM. Weight gain associated with neuroleptic medication: a review. Schizophr Bull. 1995;21:463–472. MEDLINE

[207]. [207] Kinon BJ. The routine use of atypical antipsychotic agents: maintenance treatment. J Clin Psychiatry. 1998;59:18–22.

[208]. [208] Mukherjee S, Decina P, Bocola V, Saraceni F, Scapicchio PL. Diabetes mellitus in schizophrenic patients. Compr Psychiatry. 1996;37:68–73. | CrossRef

[209]. [209] Dixon L, Weiden P, Delahanty J, Goldberg R, Postrado L, Lucksted A, et al. Prevalence and correlates of diabetes in national schizophrenia. Schizophr Bull. 2000;26:903–912. MEDLINE

[210]. [210] Kingsbury SJ, Fayek M, Trufasiu D, Zada J, Simpson GM. The apparent effects of ziprasidone on plasma lipids and glucose. J Clin Psychiatry. 2001;62:347–349. MEDLINE

[211]. [211] Klien B, Steel RI, Simon WE, Primavera LH. Reinforcement and weight loss in schizophrenics. Psychol Rep. 1972;30:581–582. MEDLINE

[212]. [212] Umbricht D. Cognitive behavior therapy for weight gain. Am J Psychiatry. 2001;158:971. CrossRef

[213]. [213] Ball MP, Coons VB, Buchanan RW. A program for treating olanzapine-related weight gain. Psychiatr Serv. 2001;52:967–969. MEDLINE | CrossRef

[214]. [214] Floris M, Lejeune J, Deberdt W. Effects of amantadine on weight gain during olanzapine treatment. Eur Neuropsychopharmacol. 2001;11:181–182. | CrossRef

[215]. [215] Sacchetti E, Guarneri L, Bravi D. H2 antagonist nizatidine may control olanzapine-associated weight gain in schizophrenic patients. Biol Psychiatry. 2000;48:167–168. Abstract | Full Text | Full-Text PDF (27 KB) | CrossRef

[216]. [216] Dursun SM, Devarajan S. Clozapine weight gain, plus topiramate weight loss. Can J Psychiatry. 2000;45:198. MEDLINE

a Department of Psychiatry, Harvard Medical School, Boston, MA, USA

b Commonwealth Research Center, Massachusetts Mental Health Center, 74 Fenwood Road, Boston, MA 02115, USA

Corresponding author. Commonwealth Research Center, Massachusetts Mental Health Center, 74 Fenwood Road, Boston, MA 02115

☆ This work was supported in part by grants to A.I.G. from NIAAA (#AA11904), NIDA (#DA13196), NIMH (#MH62157), and the Commonwealth Research Center.

PII: S0193-953X(02)00014-X

8 of 15